The present invention relates to a method for modulating, inhibiting or decreasing or preventing beta cell degeneration, loss of beta cell function, beta cell dysfunction, and/or death of beta cells, such as necrosis or apoptosis of beta cells in a subject comprising administering a GLP-1 agonist to said subject.
What most textbooks of pathology describe as cell death is coagulative necrosis. This is an abnormal morphological appearance, detected in tissue examined under the microscope. The changes, which affect aggregates of adjacent cells or functionally related cohorts of cells, are seen in a variety of contexts produced by accident, injury, or disease. Among the environmental perturbations that may cause cell necrosis are oxygen deprivation (anoxia), hyperthermia, immunological attack, and exposure to various toxins that inhibit crucial intracellular metabolic processes. Coagulative necrosis is the classical form of cell change seen when tissues autolyze (digest themselves) in vitro.
Apoptosis is an active process of cellular self-destruction that is regulated by extrinsic and intrinsic signals occurring during normal development. It is well documented that apoptosis plays a key role in regulation of pancreatic endocrine beta cells. There is increasing evidence that in adult mammalians the beta-cell mass is submitted to dynamic changes to adapt insulin production for maintaining euglycemia in particular conditions, such as pregnancy and obesity (J. Dev. Physiol. 5: 373, 1983 and Endocrinology 130: 1459, 1992). The control of beta cell mass depends on a subtle balance between cell proliferation, growth and cell death (apoptosis). A disruption of this balance may lead to impairment of glucose homeostasis. For example, it is noteworthy that glucose intolerance develops with aging when beta cell replication rates are reduced (Diabetes 32: 14, 1983) and human autopsy studies repeatedly showed a 40-60% reduction of beta cell mass in patients with non-insulin-dependent-diabetes mellitus compared with nondiabetic subjects (Am. J. Med. 70: 105, 1981 and Diabetes Res. 9: 151, 1988). It is generally agreed that insulin resistance is an invariable accompaniment of obesity but that normoglycemia is maintained by compensatory hyperinsulinemia until the beta cells become unable to meet the increased demand for insulin, at which point Type 2 Diabetes begins.
Apoptosis is also associated with diseases states such as cancer, immunological disorders, like multiple sclerosis, and AIDS, and neurodegenerative disorders (Science 267: 1449, 995), like Alzheimers disease, stroke, and Parkinson""s disease.